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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
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(±)-Integrifolin

Total Synthesis of (±)-Integrifolin

Weight control is an important concern of human beings, both for medical (pharmaceutical and/or nutraceutical) as well as non-therapeutic, e.g. cosmetic, reasons. More importantly, excessive accumulation of body fat (i.e. obesity (= adiposity), especially with excessive fat in the ventral region and surrounding the viscera) can be dangerous and has been linked to health problems such as type II diabetes, hypertension, heart disease, atherosclerosis (where more than two of the preceding disorders are present, the condition is often called “Metabolic Syndrome” or “syndrome X”), hyperlipidemia, coronary heart disease, stroke, breast and colon cancer, sleep apnoea, gallbladder disease, reproductive disorders such as polycystic ovarian syndrome, gastroesophageal reflux disease, increased incidence of complications of general anesthesia, fatty liver, gout or thromboembolism (see, e.g., Kopelman, Nature 404: 635-43 (2000)). Obesity reduces life-span and carries a serious risk of the co-morbidities listed above, as well disorders such as infections, varicose veins,

acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (Rissanen et al, Br. Med. J. 301 : 835-7 (1990)). Obesity is one of the main factors in the development of cardiovascular diseases. As a side effect the levels of cholesterol, blood pressure, blood sugar and uric acid in obese people are usually higher than those of persons of normal weight. The morbidity from coronary heart disease among the overweight people is increased as well. Among the people aged 40-50, mortality will rise about 1% when body weight increases by 0.5 kg and the death rate will increase 74% when body weight exceeds 25% of the standard. The prevalence of obesity in the United States has more than doubled since the turn of the last century (whole population) and more than tripled within the last 30 years among children aged from 6 to 11. This problem more and more becomes a disease risk also in Europe. In Germany, particularly many people have been found to suffer from overweight recently, already 25% of the young people, children and adolescents there are affected by obesity and related disorders. Furthermore, being overweight is considered by the majority of the Western population as unattractive.

Overweight and obesity result from an imbalance between the calories consumed and the calories used by the body. When the calories consumed exceed the calories burned, the body is in positive energy balance and over time weight gain will occur. The excess calories are stored in the fat cells. When the calories burned exceed the calories consumed, the body is in negative energy balance and over time weight loss will occur.

An increasing interest by consumers in the maintenance or reduction of their body weight can be found. This leads to a demand for products useful for these purposes. Preferred are such food products which can conveniently be consumed as part of the daily diet, for example meal replacer products, such as meal replacer bars and beverages. These are usually designed for use as a single-serving food product to replace one or two meals a day.

An issue is that often a saturating effect is missed when such products are consumed, resulting in hunger feelings only a relatively short time after consummation or even in the lack of a saturation feeling already directly after consummation.

Summing up, there remains a need for new safe and effective compositions for promoting weight loss and/or loss of body fat in subjects such as humans. The problem to be solved by the present invention is therefore to find compositions or compounds useful in the treatment of obesity; and/or for improving the total cholesterol HDIJLDL ratio.

Phytochemistry provides a large pool of compounds and compositions to be looked at whether they are able to solve this problem.

The present invention provides methods and compositions useful in the control, treatment and prevention of obesity and obesity-related conditions, disorders, and diseases; and/or and/or for improving the total cholesterol HDL/LDL ratio.

Rosinski, G., et al., Endocrinological Frontiers in Phyiological Insect Ecology, Wroclow Technical University Press, Wroclow 1989, describe that certain tricyclic sequiterpene lactones, such as grossheimin and repin, showed inhibition of larval growth and antifeeding activity in Mealworm (Tenebrio σιοΐϊίοή. Grossheimin shows no anti-feeding but little decrease of absorption of digested food constituents and a little decrease in efficiency in digesting. Repin exhibit low effects at all. Both compounds show no effect on lipid levels in blood.

Shimoda, H., et al, Bioinorganic & Medicinal Chemistry Letters 13 (2003), 223-228, describe that methanolic extracts from Artichoke (Cynara sclolymus L.) with cynaropicrin, aguerin B and grossheimin as components and certain sesquiterpene glycosides suppress serum triglyceride elevation in olive oil-loaded mice. Some of these compounds exhibit a moderate short term (2 hours after olive oil administration) anti-hyperlipidemic activity presented as a lowering of the serum triglyceride (serum TG) concentrations, the long term (6 hours) show in the case of cynaropicrin and aguerine B an increase of the serum TG. Furthermore the authors present data of the gastric emptying (GE) of a methanolic ectract of artichoke. They determine a significantly inhibited GE. However, as shown below, this mechanism is not an explanation for the anti obesity effect shown in the present invention (see Example 1 ).

Cynaropicrin, a tricyclic sesquiterpene lactone causes in vivo a strong weight loss. More surprisingly it was found that this effect is not correlated to a decrease in food intake. The weight balance is not affected by reduction of assimilation efficiency; the decrease of body fat and body weight is presumably caused by effects on energy metabolism. Surprisingly, it was found in addition that cynaropicrin also allows for improving the total cholesterol HDL7LDL ratio

Volutarella divaricata, Zaiuzania resinosa; and can potentially be isolated from any part of the plants. Those genera and/or species marked with an asterisk (*) and especially those species marked with two asterisks (**) are especially preferred.

Appropriate plant material can be obtained from various sources, e.g. from:

The word Unani or Yunani has its origins in the Greek word Ἰωνία (Iōnía) or Ἰωνίη (Iōníe), a place name given to a Greek populated coastal region of Ionian Sea.

History of Unani Medicine

The Origin of Unani system of medicine Is from Greece. The term ‘UNANI’ is derived from the word ‘UNAN’ or “YUNAN” which means Greece in Arabic Its also know as Greco-Arab medicine. the treatment of Unani is based on teachings of Hippocrates It was the work of the Greek philosopher-physician Hippocrates {Buqrat In Arabic} (460-377 B.C.), who freed medicine from the realm of superstition and magic and gave it the status of science. He considered illness to be natural rather than a supernatural phenomenon, and he felt that medicine should be administered without ritual ceremonies or magic.By his method of careful study and comparison of symptoms, he laid the foundation for clinical medicine.Hippocrates

After Hippocrates Many scholars enriched the system of Unani Medicine. Of them Galen {Jalinus in Arabic} (131-200 A.D.) stands out as the one who established its foundation on which Arab physicians like Rhazes {Al-Razi in Arabic} (850-932 A.D.) and Avicenna {Ibn-Sena in Arabic} (980-1037 A.D.) constructed an imposing edifice. Galen introduced and practiced the Unani system of medicine in pre-Islamic Egypt, researched, experimented and developed hundreds of new medicines and cures for almost all types of diseases.

Unani medicine was the first to establish that disease was a natural process and that symptoms were the reactions of the body to the disease. It believes in the humeral theory which presupposes the presence of the four humors – Dam (blood), Balgham(phlegm), Safra (yellow bile) and Sauda (black bile) in the body. Each humor has its own temperament – blood is hot and moist, phlegm cold and moist, yellow bile hot and dry and black bile cold and dry. Every person attains a temperament according to the preponderance in them of the humors which represent the person’s healthy state, which are expressed as sanguine, phlegmatic, choleric and melancholic.

It was further enriched by imbibing the best of contemporary systems of medicine in the middle eastern and far eastern countries like Egypt, Syria, Iraq, Persia, India, China and other Middle East and Far East countries enriched the Unani system. That is why this system is known, in different parts of the world, with different names such as Greco-Arab Medicine, Ionian Medicine, Arab Medicine, Islamic Medicine, Traditional Medicine, Oriental Medicine, etc.

A Unani physician does not prescribe the strongest drug at the beginning of the treatment. He selects the drug according to the degree of variation from the normal healthy condition and observes the effect produced by the treatment. At the same time, he instructs the patient to observe some restrictions in diet and lifestyle.“Besides the use of herbs for treatment, Unani medicine employs a variety of other techniques intended to cleanse the body and restore humor balance. These techniques include: mushil (purging), taareeq (sweating), hammam (bath therapy), munzij (ripening), mahajim (cupping) and riyazat (exercise).

Unani medicine first arrived in India around 12th or 13th century with establishment of Delhi Sultanate (1206-1527) and Islamic rule over North India and subsequently flourished under Mughal Empire. Alauddin Khilji (r. 1296-1316) had several eminent Unani physicians (Hakims) in his royal courts In the coming year this royal patronage meant development of Unani practice in India, but also of Unani literature with the aid of Indian Ayurvedic physicians.

Diagnosis and treatment

Fortunately, Unani classical literature consists of thousands of books and contains vast knowledge and mention of experiences on all aspects of medicine. According to Unani medicine, management of any disease depends upon the diagnosis of disease. In the diagnosis, clinical features, i.e., signs, symptoms, laboratory features and mizaj (temperament) are important.

Any cause and or factor is countered by Quwwat-e-Mudabbira-e-Badan (the power of body responsible to maintain health), the failing of which may lead to quantitatively or qualitatively derangement of the normal equilibrium of akhlat (humors) of body which constitute the tissues and organs. This abnormal humor leads to pathological changes in the tissues anatomically and physiologically at the affected site and exhibits the clinical manifestations.

After diagnosing the disease, Usoole Ilaj (principle of management) of disease is determined on the basis of etiology in the following pattern:

Izalae Sabab (elimination of cause)

Tadeele Akhlat (normalization of humors)

Tadeele Aza (normalization of tissues/organs)

For fulfillment of requirements of principle of management, treatment is decided as per the Unani medicine which may be one or more of the following:

Ilaj-Bil-Tadbeer wa Ilaj-Bil-Ghiza (Regimenal Therapy). The disease may be treated by the modification of six essential pre-requisites of health (Asbab-e-Sitta Zarooriya in Unani Tibbi terminology). Asbab-e-Sitta Zarooriya may be modified by the use of one or more regimens: i.e., Dalak, Riyazat, Hammam, Taleeq, Takmeed, Hijamat (Cupping Therapy), Fasd, Lakhlakha, Bakhur, Abzan, Shamoomat (Aromatherapy), Pashoya, Idrar, Ishal, Qai, Tareeq, Elam, Laza-e-Muqabil, Imalah and alteration of food. According to the norms of C.C.I.M. New Delhi, Department of Ilaj-Bil-Tadbeer has been established in almost all Unani Tibbi Colleges of India. In the State Unani Medical College, Allahabad, U.P. and State Takmeel-Ul-Tibb College, Lucknow, Department of Ilaj-Bil-Tadbeer is known as Moalijat Khususi. Moaliajt Khususi is the old nomenclature of Ilaj-Bil-Tadbeer, suggested by C.C.I.M. New Delhi. Ilaj-Bil-Tadbeer is synonym to Panchkarma in Ayurveda.

Ilaj-Bil-Advia (Pharmacotherapy). For this purpose Mamulate Matab Nuskha (prescription) is formulated which contain the single and or compound (murakkābāt) Unani drugs[12] having desired actions as per requirements.

Ilaj-Bil-Yad (Surgery)

As an alternative form of medicine, Unani has found favor in India where popular products like Roghan Baiza Murgh (Egg Oil) and Roghan Badaam Shirin (Almond Oil) are commonly used for hair care. Unani practitioners can practice as qualified doctors in India, as the government approve their practice. Unani medicine is very close to Ayurveda. Both are based on theory of the presence of the elements (in Unani, they are considered to be fire, water, earth and air) in the human body. (The elements, attributed to the philosopher Empedocles, determined the way of thinking in Medieval Europe.) According to followers of Unani medicine, these elements are present in different fluids and their balance leads to health and their imbalance leads to illness.

The theory postulates the presence of blood, phlegm, yellow bile and black bile in the human body. Each person’s unique mixture of these substances determines his Mizaj(Temperament). a predominance of blood gives a sanguine temperament; a predominance of phlegm makes one phlegmatic; yellow bile, bilious (or choleric); and black bile, melancholic.

Education and recognition

In India, there are 40 Unani medical colleges where the Unani system of medicine is taught. After five and half year courses, the graduates are awarded BUMS (Bachelor of Unani Medicine and Surgery). There are about eight Unani medical colleges where a postgraduate degree (Mahir-e-Tib and Mahir Jarahat) is being awarded to BUMS doctors. All these colleges are affiliated to reputed universities and recognized by the governments.

In India, the Central Council of Indian Medicine (CCIM) a statutory body established in 1971 under Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH), Ministry of Health and Family Welfare, Government of India, monitors higher education in areas of Indian medicine including, Ayurveda, Unani and Siddha. To fight biopiracy and unethical patents, the Government of India, in 2001, set up the Traditional Knowledge Digital Library as repository of formulations of systems of Indian medicine, includes 98,700 Unani formulations.[14][15] Central Council for Research in Unani Medicine (CCRUM) established in 1979, also under AYUSH, aids and co-ordinates scientific research in the Unani system of medicine through a network of 22 nationwide research institutes and units, including two Central Research Institutes of Unani Medicine, at Hyderabad and Lucknow, eight Regional Research Institutes at Chennai, Bhadrak, Patna, Aligarh, Mumbai, Srinagar, Kolkata and New Delhi, six Clinical Research Units at Allahabad, Bangalore, Karimganj, Meerut, Bhopal and Burhanpur, four Drug Standardisation Research Units at New Delhi, Bangalore, Chennai and Lucknow, a Chemical Research Unit at Aligarh, a Literary Research Institute at New Delhi.

Safety issues

According to WHO, “Pharmacovigilance activities are done to monitor detection, assessment, understanding and prevention of any obnoxious adverse reactions to drugs at therapeutic concentration that is used or is intended to be used to modify or explore physiological system or pathological states for the benefit of recipient.” These drugs may be any substance or product including herbs, minerals, etc. for animals and human beings and can even be that prescribed by practitioners of Unani or ayurvedic system of medicine. In recent days, awareness has been created related to safety and adverse drug reaction monitoring of herbal drugs including Unani drugs.